Unlike prototypical lentiviruses like visna and caprine arthritis-encephalitis viruses, which are mainly macrophage-tropic (M-tropic), primate lentiviruses primarily target CD4+ T lymphocytes. We previously reported that during the late phase of highly pathogenic SIV/HIV chimeric virus (SHIV) infections of rhesus macaques, when CD4+ T cells have been systemically eliminated, high levels of viremia are maintained from productively infected macrophages. The availability of several genetically different macrophage-tropic (M-tropic) SHIVs from such late stage immunocompromised animals provided the opportunity to assess whether they might contribute to the immune deficiency induced by their T-cell tropic parental viruses or possibly cause a distinct disease based on their capacity to infect macrophages. Pairs of rhesus monkeys were, therefore, inoculated intravenously with six different M-tropic SHIV preparations and their plasma viral RNA loads, circulating lymphocyte subset numbers and eventual disease outcomes were monitored. Only one of these six M-tropic SHIVs induced any disease; the disease phenotype observed was the typical rapid, complete, and irreversible depletion of CD4+ T cells induced by pathogenic SHIVs. Our failure to observe any disease during de novo infections of rhesus monkeys with functional immune systems, initiated with 5 of 6 M-tropic SHIVs of diverse origin and clonality, implies that a majority of M tropic primate lentiviruses are intrinsically attenuated and only become dangerous in immunologically compromised hosts. During the asymptomatic phase of their infections, M-tropic HIV-1, SIV and SHIV strains comprise an important virus reservoir in tissue macrophages systemically, but do not induce a unique disease based on their M tropic properties. Rather, by continuously releasing progeny virions capable of infecting and destroying CD4+ T cells, these M-tropic viruses contribute to the unrelenting impairment of the immune system and only cause symptomatic macrophage disease (e.g. affecting the CNS) during the very late stages of infection.